Itch

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.

Mechanistic theories of itch are based on neuronal specificity, stimulus intensity, and temporal or spatial discharge patterns. Traditionally, these theories are conceptualized as mutually exclusive, assuming that finding evidence for one theory would exclude the others and could sufficiently explain itch. Current experimental data primarily support the specificity or pattern theory of itch. However, in contrast to an assumed inherent exclusivity, recent results have shown that even within itch-specific pathways in the spinal cord, temporal discharge patterns are important as sustained pruriceptor is required to allow successful transsynaptic signal progression. Also, optogenetic activation of pruriceptors suggest that the combination of neuronal specificity and temporal pattern determines the sensory effect: tonic activation of pruriceptors is required to induce scratching behavior whereas short-lasting stimulation rather causes withdrawal. In addition to the mere duration of discharge, also the temporal pattern or spatial aspects could critically contribute to elicit pruritus instead of pain. Basic neurophysiological studies trying to validate neuronal theories for pruritus in their pure form provide unitary concepts leading from neuronal discharge to the itch sensation. However, the crucial clinical questions have the opposite perspective: which mechanisms explain the chronic itch in a given patient or a given disease? In trying to solve these clinical problems we should not feel bound to the mutual exclusive nature of itch theories, but rather appreciate blending several theories and also accept combinations of itch and pain. Thus, blended versions of itch theories might better suffice for an explanation of chronic itch in patients and will improve the basis for mechanistic treatment options.